1. Field of the Invention
The present invention relates to processes for the synthesis of thieno[3,2-c]pyridine derivatives, particularly ticlopidine, and specifically to an improved process for reduction of 2-(2-nitrovinyl)thiophene to form 2-(2-thienyl)ethylamine.
2. Background Information
Previous technology for the preparation of ticlopidine has entailed a low yielding, labor intensive process, employing certain potentially harzardous and expensive materials. The cost of preparing ticlopidine has, therefore, been high. It has been desired to provide improved synthetic process technology that allows for a higher conversion, reduced labor usage, and the elimination of costly, potentially dangerous materials.
A variety of synthetic approaches to making ticlopidine have been described in the art, including improvements on the various steps of such synthetic processes, e.g., as described below.
Ticlopidine was first described by Castaigne in U.S. Pat. No. 4,051,141, where the synthesis thereof was accomplished by condensation of a thieno[3,2-c]pyridine with o-chlorobenzyl chloride.
Another synthetic route involved preparation of a 2-(2-thienyl)ethanol, its conversion to 2-(2-thienyl)ethyl paratoluene sulfonate and benzylation with o-chlorobenzylamine to give N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine hydrochloride, which is cyclized to give ticlopidine free base, as described by Braye in U.S. Pat. No. 4,127,580.
Condensation of a 4,5,6,7-tetrahydrothieno[3,2-c]pyridine with o-chlorobenzyl chloride in the presence of a tertiary amine (triethylamine) was described in Japanese Kokai J6 1271-291A.
The benzylation of thieno[3,2-c]pyridine and NaBH.sub.4 reduction of resulting quaternary salts; condensation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine with o-chlorobenzyl chloride in the presence of potassium carbonate; and benzoylation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine followed by LiAlH.sub.4 reduction are described by Maffrand et al., in Eur J. Med. Chem.-Chim. Ther., 9(5), 483-6 (1974).
The use of phase transfer catalysts in alkylation/benzylation reactions is known in the literature [see, e.g., Berg et al., Acta. Chem. Scand., 26, 4130 (1972) and Ferris et al., J. Org. Chem., 44, 173 (1979)]. Synthesis of ticlopidine under such conditions is described in UK Patent Application GB 2,166,730.
Cyclization of 2-(2-thienyl)ethylamine to 4,5,6,7-tetrahydrothieno[3,2-c]-pyridine is described by Gronowitz et al. in Arkiv Kemi, 13(19), 217-227 (1970).
Cyclization of N-(2-chlorobenzyl)-2-(2-thienyl)ethyl amine with formaldehyde to form ticlopidine is shown in NL 7801-004, and cyclization with dimethoxymethane is generically disclosed in U.S. Pat. No. 4,174,448 to Bousquet et al.
The electrochemical reduction of 2-(2-nitrovinyl)thiophene to give 2-(2-thienyl)ethylamine is described in UK Patent Application GB 2,013,196A.